This proposal will investigate the role of mononuclear phagocyte (MP; microglia, perivascular and brain macrophage) function in the pathogenesis of Alzheimer's disease (AD). The linkage of this work to the others in the program project is through uncovering common mechanisms for neurodegeneration between AD and HIV-1-associated dementia (HAD). Although MP activation is a central feature of AD neuropathology, it is unknown whether MP activation is beneficial, a reaction to, or a cause of neuronal demise and cognitive dysfunction during the disease process. To address this issue, we will investigate whether: (1) MP activation is important for the initial Abeta deposition; 2) whether clearance of Abeta is dependent on secondary MP immunity and 3) if neurotrophic responses mediated by MP is necessary for the protection of the brain during disease. To test our hypotheses of disease pathogenesis we created novel MP-modified APP (MP-APP) mouse models which lack the interferon-y receptor (IFNyR-/-/APP mouse) or over-express monocyte chemotactic protein-1 in astroglial cells (MCP-1/APP mouse). These mice will serve to elucidate the consequences of MP deactivation or over-accumulate in AD pathogenesis utilizing an APP mouse model system of disease. Quantitative immunohistochemistry will be used in conjunction with behavioral analyses and measures of APP profiling to investigate the role of MP inactivation and accumulation in AD progression. This project will take full advantage of the core facilities offered within the Center for Neurovirology and Neurodegenerative Disorders and interact actively with the other projects. All together these works will serve to correlate MP activation with AD pathogenesis including cognitive dysfunction. The long-term goal of the project is to determine the role of brain immunity in the course AD. However, the work altogether, taken in the context of the projects 1, 2 and 4, J. Zheng, Y. Persidsky and H, Gendelman will serve an even more diverse role for determining relationships between brain immunity and microglial function in AD and HAD.